Guaranteeing the Safety of Pre-filled Devices in the European Union
This article was originally published in RAJ Devices
Executive Summary
Bente Lewinsky, Tove Kjær and Lars Hyveled-Nielsen say tighter regulation is required.
Bente Lewinsky, Tove Kjær and Lars Hyveled-Nielsen say tighter regulation is required.
Bente Lewinsky is specialist of regulatory affairs, medical devices and quality systems, device manufacturing and sourcing regulatory affairs at Novo Nordisk A/S. Tove Kjær is associate global project director, regulatory affairs department AERx and device projects at Novo Nordisk A/S. Lars Hyveled-Nielsen is global & regulatory affairs project director, department AERx and device projects at Novo Nordisk A/S.
It is becoming increasingly common for drug delivery systems to combine drugs and medical devices in a ready-for-use assembly. It is easy for patients to use the drugs and it is more convenient for users to transport, store and dispose of them. Handling errors are reduced and the instructions can be made more simple and easy to understand.
When devices and drugs are combined a question often arises: Is the product subject to medical device regulations or medicinal products regulations, or both? The basic requirement in the European Union (EU), Japan and the US is to ensure safe and functional pre-filled devices (ie devices intended for drug injection or inhalation) that do not cause harm to their users. But why are the requirements for the approval of the device part of these products different in the EU, Japan and the US? And do the EU regulations fulfil the basic requirement?
This article looks at the shortcomings of EU legislation with respect to the regulation of pre-filled devices and proposes a possible solution.
Overview
During the revision of Directive 93/42/EEC (Medical Devices Directive; MDD)1, stakeholders focused on the problem of making a clear distinction between medical products covered by pharmaceutical legislation, medical devices and products covered by the forthcoming regulation on advanced therapies. However, the regulation of combination products that administer a medicinal product has not been sufficiently addressed.
In the EU, devices that are placed on the market in such a way that the device and the medicinal product form a single integral product are governed by Directive 2001/83/EC (as amended) on human medicinal products2, but the relevant essential requirements of Annex I in the MDD also apply to the device part. Although Chapter 1, Section 3 of the MDD describes when device and drug constitute an integrated unit that is not for reuse, the directive does not explain how the fulfilment of Annex I must take place and who should perform the assessment of the device.
In the US, this type of product is defined as a combination product (Title 21, Part 3 of the Code of Federal Regulations (CFR))3, to be approved/registered as a drug. In Japan the products are also combination products, but the device part must be approved before being combined with the drug (Revised Pharmaceutical Affairs Law).
Combination products: EU
Pre-filled vs non pre-filled (durable) devices
Directive 93/42/EEC requires observance of Annex I, which lists the essential requirements for pre-filled devices. But how can a company document the fulfilment of these requirements? The product cannot be CE-marked. Therefore, no requirements are made regarding involvement of a notified body and, in addition, there are no requirements regarding risk classification of the product. Indirectly, requirements are made by the authority which approves the drug to ensure that the Annex I requirements are fulfilled, despite the fact that these authorities have very little knowledge of the development of medical devices.
There are no requirements in the MDD on quality systems or documentation for this type of product. This means that it is possible to manufacture a pre-filled product without a certified quality system, use of product standards, design control, technical file, declaration of conformity and notified body certification. It is possible to put pre-filled combination products on the market in the EU without fulfilling the same quality requirements of the device part that are valid for corresponding non pre-filled devices.
Combination products: non-EU
United States
A combination product in the US is assigned to a centre at the Food and Drug Administration (FDA) that will have primary jurisdiction for its premarket review and regulation. In December 2002, the FDA established the Office of Combination Products to serve as a bridge between the drug and device centres, but the primary regulatory responsibility for specific combination products remains with the “lead” centre (ie the Center for Drug Evaluation and Research, the Center for Biologics Evaluation and Research, or the Center for Devices and Radiological Health).
Under section 503(g)(1) of the Federal Food, Drug, and Cosmetic Act, as amended by the Medical Device User Fee and Modernization Act of 2002, assignment to a lead centre is based on a determination of the primary mode of action of the combination product. That centre oversees the regulation of the combination product, including the evaluation of current good manufacturing practice (GMP)4.
GMP regulatory provisions are intended to ensure that the drug, biological product or device is not adulterated, to guarantee the product possesses adequate strength, quality, identity and purity of the drug and to ensure compliance with performance standards for a device. This means that the device part of a pre-filled combination product must fulfil the same requirement as an independent device with regards to registration documentation and GMP.
Japan
Japan revised its legislation regarding devices in 20025. The revised Pharmaceutical Affairs Law requires:
- classification of medical devices and their approval or certification system;
- outline of approval and certification:
- principles of safety and performance of medical devices;
- for individual medical devices;
- documents; and
The device part of a combination product is approved in the same way as a corresponding independent device. The product is registered and the production site is audited by the Japanese authorities or third party according to device risk class prior to approving its combination with the drug.
Proposal for regulating pre-filled devices in the EU
In order to obtain safe and effective pre-filled devices in EU, the manufacturer of such combinations should have a certified quality system as required by the MDD. This would guarantee that the device part would be subject to the same requirements to documentation of development and production as non pre-filled devices. The manufacturer should prepare a self declaration of conformity to Annex I. Furthermore, the notified body should be involved for Class I devices, as these can be combined with high-risk drugs.
The result of this procedure could be confirmed by a conformity certificate issued by the notified body involved. This certificate would have to be included in the registration application for the combined product.
To aid the introduction of such a system, an EU medical device guidance document (ie a Meddev) for combination products covering pre-filled devices should be considered. Meddevs are published by the European Commission and, while they are not legally binding, they offer a common approach for manufacturers, notified bodies and competent authorities relating to questions of applying the medical device directives (the MDD, Directive 90/385/EEC on active implantable medical devices and Directive 98/79/EC on in vitro diagnostics)6. Such a document would be of great help to manufacturers, and might bring about an end to the lengthy discussions companies currently have with competent authorities on the extent and content of documentation.
References
1. EU Directive 93/42/EEC concerning medical devices, as amended, OJ, 12 July 1993, L169, 1-43
2. Consolidated Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use as amended by Directive 2002/98/EC, Directive 2004/24/EC and Directive 2004/27/EC, http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-1/consol_2004/human_code.pdf
3. US Code of Federal Regulations, Title 21, Part 3
4. Draft Guidance for Industry and FDA: Current Good Manufacturing Practice for Combination Products, September 2004, www.fda.gov/oc/combination/OCLove1dft.pdf
5. Japanese Revised Pharmaceutical Affairs Law No 96, 2002
6. European Commission, Guidelines relating to medical devices directives, http://ec.europa.eu/enterprise/medical_devices/meddev/index.htm